Dominant CD4+ T Cell Regulation Causing Chronic Infection No more than 15 percent of humans who become infected with hepatitis C virus (HCV) succeed in clearing the virus achieving a complete cure; the remaining 85 percent of HCV infected humans develop chronic viral infection. Potent CD4+ T cell responses to either the HCV/NS3 or the HCV/core proteins are critical for development of virus clearing CD8+ cytotoxic T cells. Further, the HLA-DRB1 1101,DQB 0301 alleles both present on a frequent Caucasian haplotype are associated with a better prognosis and a better chance of virus clearance in HCV infected individuals. In contrast, the equally prevalent HLA-DR7, DQ2 haplotype is associated with high risk of developing chronic viral disease after infection with HCV. The proposed research will explore how these two very common HLA haplotypes handle the HCV proteins, HCV/core and NS3 antigens differently. With the hypothesis, that the HLA-DR7, DQ2 haplotype alleles are functioning with a bias for inducing regulatory T cells, which down-regulate the virus specific T helper cell responses, we propose to study TCR repertoires, cytokine responses, and peptide/MHC binding using our HLA transgenic mouse model. We will produce HLA-DRA/DRB1 1101, DQA 0501/DQB 0301 double transgenic mice and compare their HCV specific T cell responses with a similar line of HLA class II transgenic mice with the DRA/DRB1 0701, DQA 0201/DQB 0201 alleles after immunization with recombinant HCV/core or HCV/NS3 protein. These studies, including CD4+ T cell epitope mapping, development of altered peptide ligands and attempts using peptide pulsed dendritic cells or DNA/RNA plasmids for immunization, may be directly applicable in designs of new more effective HCV vaccines for humans.